Quantitative Expression of TEL in Childhood Acute Lymphoblastic Leukemia

2004 ◽  
Vol 19 (4) ◽  
pp. 328-331 ◽  
Author(s):  
G. Timson ◽  
M.I. Gutiérrez ◽  
K. Bhatia
Keyword(s):  
Loss Of Heterozygosity ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Rt Pcr ◽  
Childhood All ◽  
Quantitative Expression ◽  
Hemizygous Deletion ◽  
Chromosome 12P ◽  
Minimal Data ◽  
Inactivating Mutations

Loss of heterozygosity of chromosome 12p in human precursor B-cell ALL invariably results in loss of TEL coding sequences. Accompanied by a 12;21 translocation, such loss of heterozygosity ensures complete loss of the wild-type TEL. No inactivating mutations of the retained TEL allele have been reported in leukemias with hemizygous deletion. However, only minimal data reported the expression of the wild-type TEL in ALL. We now demonstrate that quantitative real-time RT-PCR from leukemic RNA samples could be indicative of compromised TEL expression in childhood ALL and therefore loss of TEL function.

Genetic Polymorphisms in the Folate Pathway and Risk of Childhood Acute Lymphoblastic Leukemia (ALL): MTHFR, MTHFD1, RFC1 and TS.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2274-2274
Author(s):  
Allen Eng-Juh Yeoh ◽  
Shirley Kow-Yin Kham ◽  
Yi Lu ◽  
Toon-Chai Foo ◽  
Hany Ariffin ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Folate Metabolism ◽  
Childhood Leukaemia ◽  
Wild Type ◽  
Nucleotide Synthesis ◽  
Childhood All ◽  
Folate Pathway ◽  
The Impact

Abstract Folate is critical for DNA synthesis and methylation; dysfunction in methylating enzymes may result in genomic instability and DNA damage via the nucleotide synthesis pathways. We hypothesize that perturbation in the folate metabolism pathway may alter the risk of developing childhood leukaemia. We recently reported that methylenetetrahydrofolate reductase (MTHFR 677C>T) was associated with reduced risk in childhood ALL. We aim to explore the value of a pathway approach, in this case exploring the impact of polymorphisms in multiple enzymes involved in the folate pathway, to determine its role in development of childhood ALL. As childhood ALL is highly heterogeneous and that some like TEL-AML1 and hyperdiploid subgroups have in utero origin, we postulated that the impact of folate metabolism may be greatest for in utero onset ALL. We analyzed the methylenetetrahydrofolate dehydrogenase (MTHFD1), reduced folate carrier (RFC1) and thymidylate synthase (TSER 5′-UTR 28bp repeat, TSER 3′-UTR 6bp deletion) in 360 children with ALL and 433 controls of Chinese and Malay origin (Ch=221, Mal=212). Genotyping was performed by RFLP-PCR, TEL-AML1 by RT-PCR, and hyperdiploidy either DNA index (≥1.16) or karyotyping. The latter was only available in some patients, especially in the Chinese. Using logistic regression model analysis, MTHFR 677C>T and MTHFD1 1958G>A showed significant influence on leukemia susceptibility in the Chinese (n=235, p=0.005) and Malays (n=125, p=0.032) respectively. In the Chinese cohort, MTHFR 677 CT and TT genotypes significantly decreased risk of childhood ALL as compared to CC wild type (p=0.004, OR=0.57, 95%CI=0.39–0.83), as well as in the hyperdiploidy subgroup (n=35, p=0.002, OR=0.28, 95%CI=0.12–0.65). The combined effect of RFC 80GA and AA genotypes with MTHFR 677CC wild type also decreased risk of childhood ALL in Chinese (p=0.05, OR=0.47, 95%CI=0.22–1.0). In the Malay cohort, the MTHFR 677 CT and TT genotypes played a protective role only in the TEL-AML1 subgroup (n=27) as compared to CC wild type (p=0.05, OR=0.24, 95%CI=0.06–1.0). However, interestingly MTHFD1 1958GG wild type decreased risk of childhood ALL as compared to MTHFD1 1958GA or AA genotypes (p=0.02, OR=0.54, 95%CI=1.11–3.05) when combined with MTHFR 677CC genotype. Haplotype analysis of TSER variants showed no significant effect in the 2 races. Using a candidate pathway approach, we showed that polymorphisms in the folate pathway significantly modified the risk of developing childhood ALL especially the MTHFR, MTHFD1 and RFC1. This effect may arise from different genes of the same pathway and this may be different for different races. This supports a pathway way rather than a single-gene approach towards elucidation of cancer risk in childhood ALL.

JAK2 mutations and CRLF2 rearrangements in Down Syndrome-Associated Acute Lymphoblastic Leukemia in Japan

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1451-1451
Author(s):  
Isamu Hanada ◽  
Kiminori Terui ◽  
Tsutomu Toki ◽  
Ko Kudo ◽  
Tomohiko Sato ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
The Other ◽  
Pseudoautosomal Region ◽  
Rt Pcr ◽  
Childhood All ◽  
Western Countries

Abstract Abstract 1451 Children with Down syndrome (DS) have a 10- to 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). In DS-associated ALL (DS-ALL), the chromosome aberrations which are generally common in childhood ALL, such as hyperdiploidy and t(12;21), are less frequent. Recent studies have shown that activating JAK2 mutations and overexpression of cytokine receptor-like factor 2 (CRLF2) gene are identified in approximately 20% and 50–60% of DS-ALL in Western countries, respectively. Most of the patients with CRLF2 overexpression have been reported to be associated with interstitial deletions of the pseudoautosomal region 1 (PAR1) of the sex chromosomes and the P2RY8-CRLF2 fusion gene. In addition, one report showed that the activating CRLF2 F232C mutation was identified in about 10% of DS-ALL. However, there have been no studies to determine the incidence of these genetic aberrations in Asian patients with DS-ALL. In this study, 23 patients with DS-ALL in Japan were screened for mutations in the pseudokinase domain of the JAK2 gene, the P2RY8-CRLF2 fusion gene, and the CRLF2 F232C mutation by PCR/RT-PCR and direct sequencing. Fourteen patients, whose bone marrow RNAs were available, were also screened for CRLF2 overexpression by real-time quantitative RT-PCR. We identified the JAK2 R683G mutation in 2 patients (9%) and the P2RY8-CRLF2 fusion gene in 4 patients (17%). The CRLF2 F232C mutation was not detected in any patient. CRLF2 overexpression was observed in 2 of 14 patients examined (14%). Although bone marrow RNA was available in only 1 of 4 patients positive for P2RY8-CRLF2, high-level expression of CRLF2 was confirmed in this patient. The other patient with CRLF2 overexpression was negative for P2RY8-CRLF2, indicating the involvement of the other type of CRLF2 rearrangement, IGH@-CRLF2 in this patient. We also performed a preliminary study on JAK1, JAK3, and Interleukin-7 receptor-α (IL7R) mutations, and 14, 11, and 12 patients were screened for mutations in the pseudokinase domain of JAK1, JAK3, and exon 5 and 6 of IL7R, respectively. However, no mutations were identified in any patient. Our results show the lower incidence of CRLF2 rearrangements in DS-ALL patients in Japan than that in Western countries. Gene alterations other than CRLF2 rearrangements may contribute to leukemogenesis in Japanese patients with DS-ALL. To clarify if the incidences of the mutations in JAK1-3, CRLF2, and IL7R are also lower in DS-ALL patients in Japan than those in Western counties, more patients need to be studied. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Extra Copies of der(21)t(12;21) plus Deletion ofETV6Gene due to dic(12;18) in B-Cell Precursor ALL with Poor Outcome

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Marina Araújo Fonzar Hernandes ◽  
Terezinha de Jesus Marques-Salles ◽  
Hasmik Mkrtchyan ◽  
Eliane Maria Soares-Ventura ◽  
Edinalva Pereira Leite ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Good Prognosis ◽  
Chromosome 21 ◽  
Cell Precursor ◽  
Childhood All ◽  
Molecular Cytogenetic ◽  
Cytogenetic Studies ◽  
Chromosome 12P

Acute lymphoblastic leukemia (ALL), CD10+ B-cell precursor, represents the most frequent type of childhood ALL from 3 to 6 years of age. The t(12;21)(p13;q22) occurs in 25% of cases of B-cell precursor ALL, it is rare in children less than 24 months and have been related to good prognosis. Some relapse cases and unfavorable prognosis in ALL CD10+ are associated with t(12;21) bearing additional aberrations as extra copies of chromosome 21 andETV6gene loss. This report describes the case of a 15 month-year old girl, who displayed a karyotype with addition on chromosome 12p plus trisomy 10 and tetrasomy of chromosome 21. Molecular cytogenetic studies revealed two extra copies of the der(21) t(12;21), trisomy 10 and deletion of the secondETV6gene due to the dic(12;18). These findings show the great importance of molecular cytogenetic studies to clarify complex karyotypes, to define prognostic, to carry out risk group stratification and to support correctly disease treatment in childhood acute lymphoblastic leukemia.

scholarly journals Translocation ETS leukemia-acute myeloid leukemia 1 (TEL-AML1) gene fusion in childhood acute lymphoblastic leukemia

2009 ◽  
Vol 49 (5) ◽  
pp. 270
Author(s):  
Sri Mulatsih ◽  
Yeow Liang ◽  
Allen Yeoh ◽  
Sutaryo Sutaryo ◽  
Sunarto Sunarto
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Gene Fusion ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Molecular Characteristics ◽  
Rt Pcr ◽  
Cross Sectional ◽  
Childhood All ◽  
Diagnostic Quality ◽  
Aml1 Gene

Background Acute lymphoblastic leukemia (ALL) in childrenis a heterogeneous disease with different subtypes based on their cellular and molecular characteristics. This condition wouldinfluence the treatment outcome and subsequent risk for relapse. Accurate assignment of individual patients to risk groups is a critical issue for better outcome. TEL-AML1 gene fusion is themost frequent in childhood ALL.Objective The aim of this study was to investigate the incidenceofTEL-AML1 children with ALL in Sardjito Hospital.Methods This was a cross sectional study. In this preliminarystudy, we used nested reverse-transcriptase polymerase chainreaction (RT-PCR) to analyze the present of TEL-AML1 genefusion in bone marrow sample of childhood ALL patients.Results We analyzed 41 samples. Out of these, 30 (73%) wereamplified. Twenry three out of 30 ALL patients with good medicalrecord were analyzed for this gene fusion. Out of 30 patients, there were five patients (17%) with TEL-AML1-positive gene fusion and 25 (83%) were TEL-AML1-negative. Among five patients with TEL-AML1-positive gene fusion, four patients (80%) were one year to less than 10 year old. All of the patients (100%) were with leukocyte < 50x109/L.Conclusions TEL-AML1 gene fusion was found in 17 % ofsamples. This gene fusion was more frequent in standard risk group (based on age and leukocyte). These data must be clarified with more samples. RT-PCR must be apply in all center as one part of improving diagnostic quality, especially in managing leukemia patients.

Thiopurine Methyltransferase Genetics Is Associated with Treatment Outcome and Hepatic Toxicity in Pediatric Patients with Acute Lymphoblastic Leukemia: a Report From the ALL-BFM Study Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2625-2625
Author(s):  
Martin Stanulla ◽  
Elke Schäffeler ◽  
Silke Pohlschmidt ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Thiopurine Methyltransferase ◽  
Wild Type ◽  
Childhood All ◽  
Genotype 2 ◽  
Minimal Residual

Abstract Abstract 2625 Poster Board II-601 The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) play an essential role in treatment protocols for acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurines and underlies phenotypically relevant genetic variation. Heterozygotes or homozygotes for TPMT genotypes conferring lower enzyme activity demonstrate thiopurine drug metabolic patterns distinct from those of TPMT wild-type individuals. Underlining its clinical importance, several studies have demonstrated a relationship between low TPMT enzyme activity and thiopurine-associated toxicity as well as decreased relapse risk. Here we report on a prospective evaluation of the role of TPMT genetics for survival and treatment-related toxicity in a cohort of 814 pediatric ALL patients. These 814 patients were initially selected based on availability of DNA and represent 85.1% of the entire patient population (n=956) enrolled in the German-Austrian-Swiss multi-center trial ALL-BFM 2000 from October 1999 to September 2002. Genotyping for TPMT was performed by a denaturing HPLC method and subsequent sequencing of variant alleles using DNA prepared from either leukemic or remission bone marrows. This analysis revealed 755 (92.8%) patients with TPMT wild-type, 55 (6.8%) with a heterozygous, and 4 (0.5%) with a homozygous variant genotype (*2/*3A, *3A/*3A [n=2], *3A/*11), respectively. Genotype frequencies were in Hardy-Weinberg equilibrium. Allele frequencies were as follows: TPMT*1 = 96.12%, TPMT*2 = 0.25%, TPMT*3A = 2.95%, TPMT*3C = 0.56%, TPMT*9 = 0.06%, and TPMT*11 = 0.06%. Patients (n=55) heterozygous for allelic variants of TPMT conferring lower enzyme activity demonstrated significantly better event-free survival (EFS) and a lower relapse rate compared to homozygous wild-type patients (n=755) (six-years pEFS; heterozygotes vs. wild-type, 95% (SE 3%) vs. 84% (SE 1%), p(log-rank) = 0.04; p(point estimate difference) = <0.001, relapse incidence at six years, 4% (SE 3%) vs. 12% (SE 3%), p = 0.07). In a Cox regression analysis, adjusting for sex, age, presenting leukocyte count, immunophenotype and minimal residual disease the effect of TPMT genotype was still detectable, but lost statistical significance (hazard ratio for TPMT heterozygosity = 0.38, p = 0.10). An analysis stratified by minimal residual disease-defined risk groups will be presented. While TPMT heterozygotes did not demonstrate statistically significant differences when their toxicity data collected according to the National Cancer Institute's Common Toxicity Criteria were compared with wild-type patients for 6-MP-containing treatment phases, they had an increased risk of developing hepatic veno-occlusive disease associated with a two-week exposure towards 6-TG given during re-intensification. In conclusion, TPMT genotyping may contribute important information for clinical decision making in childhood ALL that goes beyond the prevention of toxicity in TPMT deficient patients. Disclosures: No relevant conflicts of interest to declare.

Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1045-1049 ◽  
Author(s):  
Wim J. E. Tissing ◽  
Jules P. P. Meijerink ◽  
Bas Brinkhof ◽  
Mathilde J. C. Broekhuis ◽  
Renee X. Menezes ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Childhood All ◽  
Taqman Technology ◽  
Promoter Usage ◽  
Polymerase Chain

Abstract Glucocorticoid (GC) resistance is an adverse prognostic factor in childhood acute lymphoblastic leukemia (ALL), but little is known about causes of GC resistance. Up-regulation of the glucocorticoid receptor (GR) has been suggested as an essential step to the induction of apoptosis in leukemic cells. In this study we investigated whether baseline mRNA expression levels of the 5 different GR promoter transcripts (1A1, 1A2, 1A3, 1B, and 1C) or differences in the degree of regulation of the GR or GR promoter transcripts upon GC exposure are related to GC resistance. Therefore, mRNA levels of the 5 GR promoter transcripts and of the GR were measured by quantitative real-time reverse transcriptase–polymerase chain reaction (RT-PCR; Taqman) technology in primary ALL cells prior to and after 3, 8, and 24 hours of prednisolone exposure. GR expression is induced upon GC exposure in primary ALL patient samples, which is opposite to what is found in tissues in which GCs do not induce apoptosis. GC resistance in childhood ALL cannot be attributed to an inability of resistant cells to up-regulate the expression of the GR upon GC exposure, nor to differences in GR promoter usage (at baseline and upon GC exposure).

scholarly journals Molecular Cytogenetics in Childhood Acute Lymphoblastic Leukemia: A Hospital-Based Observational Study

2015 ◽  
Vol 9 ◽  
pp. CMO.S24463 ◽  
Author(s):  
Aakash Pandita ◽  
Rekha Harish ◽  
Sanjeev K. Digra ◽  
Alok Raina ◽  
Annie Arvind Sharma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cytogenetic Analysis ◽  
Lymphoblastic Leukemia ◽  
Care Hospital ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Childhood All ◽  
Molecular Cytogenetic ◽  
Molecular Abnormalities

Objective This study was conducted to determine the frequency of chromosomal aberrations in children aged <19 years with newly diagnosed acute lymphoblastic leukemia (ALL), attending/admitted in the Department of Pediatrics and Radiotherapy, Government Medical College, Jammu. Furthermore, we aimed to study the correlation between the cytogenetic molecular abnormalities and the immediate clinical outcome (induction of remission). Materials and Methods This was a prospective study conducted over a period of 2 years (May 2011 to May 2013) in a tertiary care hospital in India. Forty pediatric (1–19 years) patients (18 males, 22 females; M: F = 0.8: 1) with newly diagnosed ALL were studied for molecular cytogenetic analysis. Written consent was obtained from the parents of the patients. Bone marrow aspiration was done for making the diagnosis of ALL. Children lost to follow-up and who failed to give consent were excluded from the survey. Host factors and clinical parameters were obtained from patients. Results Bone marrow aspirate samples of 40 diagnosed cases of ALL were subjected to routine cytogenetic analysis, and reverse transcription-polymerase chain reaction (RT-PCR) technique was used for molecular analysis. Well-spread metaphase plates were obtained in 18/40 (45%) cases for analysis. RT-PCR revealed abnormal genes in 20/40 (50%) patients. The results of molecular cytogenetic analysis were correlated with patients’ clinical and hematological parameters for risk stratification and immediate outcome (induction of remission). Eighteen out of 40 (45%) cases revealed no abnormality. Among the remaining 22 cases, 8 had TEL–AML1 (20%), 6 had BCR–ABL (15%), 4 had MLL–AF4 (10%), 2 had E2A–PBX1 (5%) fusion genes, and 2 had hyperdiploidy. To conclude, a higher proportion of cases in this study showed adverse translocations such as t (9;22), t (4;11), and t (1;19) compared to that reported in literature. Conclusion RT-PCR assay was useful in detecting the prognostically significant oncogene fusion transcripts. In our study of 40 patients, we found that the pattern and frequency differ from those reported in Western literature. Our study reveals a lower frequency of hyperdiploidy (5%) and a higher frequency of BCR–ABL gene fusion (20%) in childhood ALL. Above all, in contrast to previous studies on childhood ALL, our study showed female predominance, with the male-to-female ratio being 0.8: 1. Apart from the BCR–ABL fusion gene, none other was associated with poor prognosis. It is already well established that the characterization of the genetic entities at diagnosis is crucial for the understanding and the optimal treatment of ALL. Because the aberrations in our population differ significantly from those reported in Western populations, we may be required to tailor our protocols.

Ultra Rapid, One Step Molecular Detection of BCR-ABL Major and Minor Transcripts by Isothermal RT-Loop Mediated Amplification Reaction.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2515-2515
Author(s):  
Elena D'agostini ◽  
Giulia Minnucci ◽  
Giulia Amicarelli ◽  
Cinzia Pultrone ◽  
Veronica Tettamanzi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Molecular Detection ◽  
Lymphoblastic Leukemia ◽  
Internal Quality ◽  
Clinical Samples ◽  
Wild Type ◽  
Rt Pcr ◽  
Automatic Instrument ◽  
Fusion Transcripts ◽  
One Step

Abstract Abstract 2515 Background: The molecular identification of the BCRABL transcripts in clinical samples is actually based on a conventional Reverse Transcription Polymerase Chain reaction (RT-PCR). Here we present a novel molecular method, based on Loop Mediated Amplification assay that, starting from RNA (RT-LAMP) in one single tube reaction ensures a rapid and simultaneous detection of either the BCR-ABL p190 or p210 fusion transcript as well as the housekeeping gene used as internal quality control. Methods: The BCR-ABL RT-LAMP is a multiplex, isothermal method for retro-transcription, amplification and detection of the Minor (p190) and Major (p210) t(9;22) transcripts and the endogenous Gusb RNA, as internal control for validation of negative results. The employment of fluorescent specific probes allows real-time monitoring of the reaction, so that the test result is obtained in a single, homogeneous step. RT-LAMP is carried out on the Liaison IAM, a 8-wells manageable instrument suitable for isothermal reactions. Liaison IAM incubates at constant temperature, monitors the fluorescent signals and the data produced can be analyzed, upon connection to up to 6 other instruments, for a throughput of 8 to 48 samples. Thanks to the three channels of fluorescence, it can monitor multiplex assays, providing elaborated final objective results with no need of further data analysis by the operator. Results: The level of sensitivity of the triplex BCR-ABL RT-LAMP has been analytically evaluated directly on serial dilutions of RNA extracted respectively from t(9;22) positive cell lines (TOM-1 for p190 or K-562 for p210) into wild type RNA from HL-60 cell line (30 replicates). The p190 and p210 transcripts have been detected and distinguished down to 10−4 and 10−5respectively within 50 minutes. The assay demonstrated 100% specificity since 70 replicates of wild type RNA from 7 cell lines resulted BCR-ABL negative and GUSb positive (internal amplification control). This assay was validated on 60 clinical samples (30 white blood cells RNA from Chronic Myeloid Leukemia, 30 mononuclear cells RNA from B-lineage Acute Lymphoblastic Leukemia). All these samples were obtained at diagnosis and were previously analyzed by conventional RT-PCR. RT-LAMP detected and identified the BCR-ABL fusion transcripts correctly in all cases with a 100% concordance with the reference method. Fully concordant results were obtained also on 30 RNA samples from patients affected by t(9;22) negative hematologic malignancies and on 30 RNA samples obtained from healthy donors in which the RT-LAMP amplified exclusively the housekeeping GUSb transcript. Conclusions: The triplex p190-p210-GUSb RT-LAMP is a one-step procedure for specific, highly sensitive and rapid molecular detection of the BCR-ABL fusion transcripts. The semi-automatic instrument Liaison IAM, simplifies the entire procedure, reduces the contamination risks deriving from the conventional, multi step RT-PCR and significantly improve the diagnostic lab routine. Disclosures: D'agostini: DIASORIN S.p.A: Employment. Minnucci:Diasorin S.p.A.: Employment. Amicarelli:DIASPRIN S.p.A.: Employment. Pultrone:DIASORIN S.p.A.: Employment. Tettamanzi:DIASORIN S.p.A.: Employment. Salmoiraghi:DIASORIN S.p.A.: Consultancy. Spinelli:DIASORIN S.p.A: Consultancy. Colotta:DIASORIN S.p.A: Employment. Rambaldi:DIASORIN S.p.A: Consultancy.

scholarly journals Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 38-44 ◽  
Author(s):  
K Stegmaier ◽  
S Pendse ◽  
GF Barker ◽  
P Bray-Ward ◽  
DC Ward ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Loss Of Heterozygosity ◽  
Gene Locus ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Chromosome Band ◽  
Loss Of Function ◽  
Childhood All

TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin- dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.

scholarly journals The Prevalent, Features and Prognostic Impact of Deletion p16 in Patients with Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5351-5351
Author(s):  
Na Xu ◽  
Yulin Li ◽  
Xuan Zhou ◽  
Liu Xiaoli ◽  
Hongsheng Zhou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Significant Difference

Abstract Background and objective: Deletion of chromosome 9p21 is a crucial event for acute lymphoblastic leukemia (ALL). 9p21.3 genes encode three cell cycle inhibitory proteins: p15INK4b, p16CDKN2A, and p14ARFT. Recently studies show that p16 (CDKN2A) alleles were hypermethylated at CpG islands in ALL patients and delation p16 was associated with poor prognosis in childhood ALL. However, the prognostic significance of the deletion p16 in adult ALL leukemia is controversial, so the aim of the present study was to investigate the prevalence, feature and specific prognostic relevance of delation p16 in Chinese ALL patients from a single center in China. Patients and Methods: A total of 513 newly diagnosed adult ALL patients were identified retrospectively from the database of ALL between January 2008 and December 2013 at our center. We Detected delation p16 by interphase fluorescence in ituhybridization (I-FISH) and analyzed their clinical data retrospectively. Results: Of 513 cases, the prevalence of having either heterozygous or homozygous p16 deletions was 32%. p16 deletion were identified in 27% of newly diagnosed Philadelphia positive(Ph+) patients by univariate analysis, patients with p16 deletion had no significant difference compared with wild-type patients in terms of sex, age, white blood cells (WBC) count at diagnosis,BM blast percentage,chromosome karyotype,extra infiltration and CR I rate. The patients with p16 deletion was more likely to relapse comparaed with wild-type patients (P=0.03), and at relapse, we found a strong trend in the detection rate of p16 loss (41%) compared with diagnosis (P=0.01), suggesting that loss of this genomic region may be involved in disease progression. Of note, in newly diagnosed Ph+ALL with delation p16 were likely relapse even in the patients who treated with allogeneic hematopoietic stem cell transplantation (P=0.03). In addition, deletion p16 were significantly associated with poor outcomes in terms of overall survival (P=0.01), disease free-survival (P< 0.001), and cumulative incidence of relapse (P< 0.001). Conclusion: In our study, the absence of p16 expression seems to a poor prognostic marker in adult ALL patients. However, how to improve the survival of these patients need further study. Disclosures No relevant conflicts of interest to declare.

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